Predictive population balance modeling of pharmaceutical tablet disintegration and dissolution behavior

Predicting tablet disintegration and dissolution remains challenging due to the complex and nonlinear interplay of critical material attributes (CMAs) and physicochemical properties. This study introduces a population balance model (PBM) framework to simulate the disintegration and dissolution of tablets produced via granulation and direct compression while reducing the required experimental dataset. The framework captures the influence of CMAs, including crystal size distribution (CSD), granule size distribution (GSD), tablet and granule porosity, manufacturing routes, and active pharmaceutical ingredient (API) solubility. For granule-based tablets, an integrated system of three PBMs characterizes the number density evolution of (i) granules bound within the tablet, (ii) granules released into the solvent, and (iii) crystals. Two breakage kernels describing tablet break-up and granule fragmentation incorporate tablet porosity, granule size and porosity, and swelling-driven diffusion effects. Dissolution of crystals and granule surface erosion are modeled using a modified Noyes-Whitney equation. Experimentally determined GSD and CSD are used as initial conditions and model inputs. This framework can also be simplified into two PBMs to simulate dissolution behavior of direct compression tablets. Model accurately reproduced the dissolution behavior of acetaminophen, indomethacin, and lomustine tablets prepared via dry granulation and direct compression, with similarity factor f₂ values above 50 between predicted and experimental profiles. The semi-mechanistic nature of the framework provides mechanistic insight into dissolution behavior while reducing the need for extensive dissolution data, which may facilitate and accelerate tablet formulation development.